There has been considerable interest in the role of toll-like receptor (TLR) signaling in the host response to gastrointestinal injury. Cyclooxygenase-2 expression and PGE2 production are important downstream events in this process. The ligands typically associated with TLRs are microbial products; however, TLRs can also bind host molecules. In particular, TLR4 binds hyaluronic acid. Hyaluronic acid is a glycosaminoglycan that is produced by many cell types and is released into the extracellular space where it acts as a component of the extracellular matrix. An important role for hyaluronic acid binding to TLR4 has been described in non-microbial injury models in the lung and skin but the role of hyaluronic acid in the host response to gastrointestinal injury has not been explored. We have developed preliminary data demonstrating that: 1. Hyaluronic acid is produced in response to gastrointestinal injury in the DSS colitis model and in radiation injury in the small intestine. 2. Hyaluronic acid decreases the severity of DSS colitis. 3. In radiation injury in the small intestine, hyaluronic acid decreases radiation-induced apoptosis and increases crypt survival. These findings have lead to the following hypotheses. 1. Hyaluronic acid is generated in response to gastrointestinal mucosal injury and is a stimulus for epithelial proliferation and repair. Hyaluronic acid acts through TLR4 and perhaps TLR2 in mediating the protective response of the host in gastrointestinal injury. Moreover COX-2 expression and PGE2 production are important downstream signaling events in this process. 2. Administration of hyaluronic acid as a pharmacologic agent has preventive or therapeutic utility in gastrointestinal injury. Here we propose the following Specific Aims: 1) To define the mechanism by which HA synthesis is induced during gastrointestinal injury. 2) To define the mechanisms by which HA affects the host response to epithelial injury. 3) To define the potential role of exogenous HA as a preventive or therapeutic pharmacologic agent in models of gastrointestinal injury including DSS colitis and radiation injury in the small intestine. PUBLIC HEALTH RELEVANCE: This proposal is most directly relevant to the development of radioprotective agents (agents that would protect normal intestine during radiation therapy) and the development of agents that would increase the growth of the intestine after resection. This proposal is also relevant to any disease that involves the host response to injuries to the intestinal epithelium including inflammatory bowel disease and enteric infections.